Suicide has traditionally been considered an extreme psychological reaction to depression. More recently evidence has emerged suggesting a biological contribution. We postulated an association between reduced presynaptic serotonergic function and violent suicide. In the first 18 months of funding we have: (1) replicated our original finding of an increased number of 5-HT2 binding sites in suicide brains and (2) made the additional important finding of an increased number of cortical beta- adrenergic binding sites; (3) shown that these two measures have potential in discriminating violent homicide and suicide victims. We have developed methods that substantially enhance our ability to study monoaminergic systems in postmortem brain tissue. These include: (1) procedure for collecting suicide brains so as to permit good quality histology; (2) a combination of radioligand binding indices (Bmax and KD) in membranes and quantitative receptor autoradiography for multiple monoamine receptor subtypes in selected brain regions; (3) a method for co-localization in fresh frozen human postmortem brain tissue by dual labeling of adjacent brain secretions by immunocytochemistry and receptor autoradiography; (4) preliminary irreversible photoaffinity labeling of BZD receptors that permit very high resolution receptor imaging. Our current proposal aims to establish: (1) whether alterations in the serotonergic system in violent suicide victims are localized to specific regions in the nervous system by a combination of regional measures including quantitative autoradiography and immunocytochemistry; (2) the specificity of alterations in the serotonergic system by contrast with other transmitter systems in particular the noradrenergic system; (3) the specificity of these neurochemical changes for suicide versus a depressive illness. Overall, these studies should define in detail the extent and specificity of the serotonergic changes in suicidal behavior in terms of brain region and compared to other neurotransmitter systems. The possibility that a highly specific alteration of the serotonergic system may underlie suicidal behavior, independent of the presence of Major Depression, has profound consequences for conceptualizing the basis of human behavior as well as important implications for developing an effective specific pharmacotherapy of suicide, the cause of death of 25,000 persons per year in the United States.